We are interested in the role of endogenous opiate peptides, called endorphins, in central nervous functioning in general and in mental illness in particular. Much of our work has centered around FK 33-824, a synthetic enkephalin analogue which can be administered parenterally and orally and hence may be of use clinically. Animal studies have included demonstration of FK 33-824 inhibition of conditioned avoidance responding in rats and blockade of anxiety behavior and increase in serum prolactin in monkeys. These results suggest an interaction of FK 33-824 with brain dopamine and norepinephrine systems and possible antipsychotic and antianxiety properties in man. In patients with affective disorder and schizophrenia a double-blind placebo controlled trial of beta-endorphin is underway, and a similar trial of FK 33-824 is planned. Another strategy for identifying the role of the endorphin system is to study the effects of the opiate antagonist naloxone. We are measuring the neuroendocrine effects of naloxone in volunteers, and have shown little effect of naloxone in mania.